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Clinical Medicine Insights:

Ear, Nose and Throat

Impact of Treatment Time on the Survival of Patients Suffering From Invasive

Fungal Rhinosinusitis
Patorn Piromchai and Sanguansak Thanaviratananich
Department of Otorhinolaryngology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.

ABSTR ACT
BACKGROUND: Invasive fungal rhinosinusitis is an uncommon disease with high mortality rates. There is currently no consensus on the best treatment
timing. We studied the impact of the treatment timing on the survival of patients experiencing invasive fungal rhinosinusitis.
METHODS: We conducted a retrospective study of patients suffering from invasive fungal rhinosinusitis. The duration of symptoms, clinical presentations, clinical signs, diagnoses, treatments, and outcomes were collected.
RESULTS: It was observed that more than 70% of the mortalities occurred within the subgroup of patients who exhibited symptoms of the disease within
14 days before admission.
After adjusting for the confounders, the time taken to treat the patients was the most statistically significant predictor for mortality (P = 0.045). We found
no significant relationships between mortality and its significant covariates, which included the underlying diseases (P = 0.91) or complications (P = 0.55).
CONCLUSIONS: Our study demonstrates that the time taken to treat the patients is an important determinant for the survival of patients who are
afflicted with invasive fungal rhinosinusitis. The appropriate treatments should be administered within 14 days from the time the symptoms begin to
manifest.
KEY WORDS: sinusitis, rhinosinusitis, fungus, treatment, survival
CITATION: Piromchai and Thanaviratananich. Impact of Treatment Time on the Survival of Patients Suffering From Invasive Fungal Rhinosinusitis. Clinical Medicine Insights:
Ear, Nose and Throat 2014:7 3134 doi:10.4137/CMENT.S18875.
RECEIVED: July 22, 2014. RESUBMITTED: July 31, 2014. ACCEPTED FOR PUBLICATION: August 8, 2014.
ACADEMIC EDITOR: Brenda Anne Wilson, Editor in Chief
TYPE: Original Research
FUNDING: Authors disclose no funding sources.
COMPETING INTERESTS: Authors disclose no potential conflicts of interest.
COPYRIGHT: the authors, publisher and licensee Libertas Academica Limited. This is an open-access article distributed under the terms of the Creative Commons
CC-BY-NC3.0License.
CORRESPONDENCE: patorn@gmail.com
This paper was subject to independent, expert peer review by a minimum of two blind peer reviewers. All editorial decisions were made by the independent academic editor. All authors
have provided signed confirmation of their compliance with ethical and legal obligations including (but not limited to) use of any copyrighted material, compliance with ICMJE authorship
and competing interests disclosure guidelines and, where applicable, compliance with legal and ethical guidelines on human and animal research participants.

Introduction

Invasive fungal rhinosinusitis is an uncommon disease with

high mortality rates. Up to 80% of invasive fungal rhinosinusitis patients experienced death or further morbidities after the
treatment of the disease was completed (ranging from 20 to
80%).13 The aggressive and progressive nature of the disease
necessitates that diagnosis and treatment must occur rapidly.
The histologic evidence of fungi in hyphal forms invading the
sinus mucosa and beyond, such as the submucosa, the blood
vessels, or the bone, was needed to make the diagnosis of
invasive fungal rhinosinusitis. The standard treatment usually
comprises surgical debridement and anti-fungal therapy.

Invasive fungal rhinosinusitis can be subdivided into acute

and chronic invasive fungal rhinosinusitis. Some authors created a further subdivision within chronic invasive fungal rhinosinusitis by defining certain cases as granulomatous invasive
fungal rhinosinusitis;4,5 however, the pathological distinction
between chronic and granulomatous invasive fungal rhinosinusitis does not change the management of the disease.
The pathogenesis of acute invasive fungal rhinosinusitis was from the aggressive pathogenic fungi in the nasal
or sinus cavities invading the mucosa. The fungal cells can
spread to surrounding structures such as the eyes and the
brain via the blood vessels. The histology of acute invasive

Clinical Medicine Insights: Ear, Nose and Throat 2014:7

31

Piromchai and Thanaviratananich

fungal rhinosinusitis usually shows that it is a highly necrotic,

abundantly neutrophilic and angiotrophic process.6,7 Acute
invasive fungal rhinosinusitis is classified differently from
chronic invasive fungal rhinosinusitis, with a period of less
than 4 weeks separating the two types of diseases.8 Chronic
invasive fungal rhinosinusitis results from a less aggressive
spreading of the fungal cells, in comparison with acute invasive
fungal rhinosinusitis. The histology usually consists of a lowgrade mixed cellular infiltrate in affected tissues.6,7
The invasion of the fungi usually spreads beyond the sinus
cavity into the orbit and the intracranial space. Orbital complications include preseptal cellulitis, orbital cellulitis, subperiosteal abscesses, and orbital abscesses. Intracranial complications
include epidural or subdural abscesses, brain abscesses, meningitis, encephalitis, and cavernous sinus thrombosis.
The diagnosis of invasive fungal rhinosinusitis is usually
delayed because the detection of fungal cultures or pathological results requires a few days to a few weeks to complete.
Therefore, the presentations and the clinical findings obtained
from the patients are important determinants. An early detection of fungal invasion will allow for better management and
better prognosis for the patient.
There was no consensus on the best treatment timing. We
studied the impact of the treatment timing on survival of the
patients with invasive fungal rhinosinusitis. We hypothesize
that an earlier treatment would be associated with improved
survival. This study could also be useful for the rhinosinusitis
workgroups to work with.

Methods

Study design and setting. We retrospectively reviewed a

cohort of patients afflicted with invasive fungal rhinosinusitis.
Data spanning a period of 11years were extracted from the
university hospital database (19972008). This hospital is the
most prominent university hospital in the northeastern region
of Thailand. Most patients suffering from invasive fungal rhinosinusitis were referred to our hospital.
Case definition. Rhinosinusitis was defined as an inflammation of the nasal cavities and the paranasal sinuses and is
characterized by two or more symptoms, which should be a
nasal blockage, an obstruction, a congestion, or a discharge
(anterior/posterior nasal drip), which may have accompanying facial pain/pressure and reduction, or loss, in the sense
of smell. These symptoms should be supported by a demonstrable disease that includes any of the following observations:
endoscopic signs of nasal polyps, mucopurulent discharge
primarily from the middle meatus, edema/mucosal obstruction primarily in the middle meatus, or imaging of mucosal
changes within the ostiomeatal complex and/or sinuses.9,10
Invasive fungal rhinosinusitis was defined as the pathological results indicating the invasion of fungi into the nasal
mucosa, sinus mucosa, or deeper tissues.
Data collection. We collected the data from our rhinosinusitis registry, outpatient department cards, and admission
32

records. The duration of symptoms, clinical presentation,

clinical signs, diagnoses, treatments, and treatment outcomes
were noted in a standardized checklist.
Statistical analysis. The categorical variables were presented in the form of frequencies and percentages. The association between categorical variables was assessed using the
chi-square test. The continuous variables were presented in
the form of means. The Cox proportional hazards regression
was used to adjust for potential confounding in the association between time to treatment and in-hospital mortality. We
considered underlying diseases and complications as potential
covariates, with a P value of less than 0.05 being considered
statistically significant. All statistical analyses were performed
using the Statistical Package for the Social Sciences (SPSS
Inc., Chicago, IL) software program, Version 20.0.
Ethics. The Khon Kaen University Ethics Committee for
Human Research approved this project before it was initiated.

Results

From 1997 to 2008, 59 patients were diagnosed with invasive

fungal rhinosinusitis. Forty-five patients suffered from acute
invasive fungal rhinosinusitis, while the other 14 suffered
from chronic invasive fungal rhinosinusitis (76.3 and 23.7%,
respectively). The male and female proportion within the
patients was not significantly different (26 male vs 33 female).
The ages of the patients ranged from 16 to 78 years, with a
mean age of 51.7years. More than 60% of patients also suffered from diabetes mellitus as an underlying disease. Most of
the 59 patients were found to have the fungi spreading beyond
the nasal and sinus cavities (76.2%). The complications ranged
from orbital cellulitis to cavernous sinus thrombosis (Table 1).
All patients received the standard treatment of endoscopic
or external approach debridement and intravenous amphotericin B. One-third of the patients in the acute invasive fungal
rhinosinusitis group did not survive the disease (31.1%), while
all patients in the chronic invasive fungal rhinosinusitis group
survived.
The majority of the events occurred within the subgroup of
patients who exhibited symptoms of the disease within 14days
before admission. In the group of patients who exhibited the
symptoms for 17days before admission, 6 out of 20 patients
did not survive (30%). In the group of patients who exhibited the
symptoms for 814days before admission, 5 out of 15 patients
did not survive (33.3%), as is shown in Table 2.
The survival function graph analyzed the probabilities of surviving at any specific point in time. We found that
the probability of survival decreased rapidly within the first
14days (Fig. 1).
After adjusting for the confounders in the Cox proportional hazards regression model, the time to treatment was the
statistically significant predictor for mortality (P=0.045). For
the covariates, we found no relationship between the underlying diseases (P=0.91) and complications (P=0.55) as the
significant covariates for mortality.

Clinical Medicine Insights: Ear, Nose and Throat 2014:7

Treatment time impact on survival of invasive fungal rhinosinusitis patients

Table 1. Baseline characteristics of patients.

1.00

CHRONIC
INVASIVE
FUNGAL
RHINOSINUSITIS
(n = 14)

Sex (male:female)

20:25

6:8

Age (mean)

52.27 (1678)

49.86 (3271)

0.99

Cum survival

ACUTE INVASIVE
FUNGAL
RHINOINUSITIS
(n = 45)

0.98

0.97

Underlying diseases
DM

30

Hematologic
malignancy

Renal failure

SLE

Preseptal cellulitis

Orbital cellulitis

12

Orbital abscess

Cavernous sinus
thrombosis

16

Intracranial
involvement

0.96
0

10

15

20

25

30

Symptom duration

Complications

Figure 1. Survival function of invasive fungal rhinosinusitis patients.

Discussion

Invasive fungal rhinosinusitis is a disease that is difficult to

treat. Our recent studies11,12 and other reviews13,14 have found
that invasive fungal rhinosinusitis can present itself with a
wide variety of symptoms and signs. These different signs and
symptoms make the initial diagnosis of the disease difficult.12
A complete history taking, a knowledge of any underlying
diseases (especially for patients who have their immunities
compromised), a physical examination, and an awareness of
these conditions will eventually lead to a diagnosis and rapid
treatment of this aggressive disease.
However, the question of how prioritized the treatment
should be has gone unanswered. We have usually regarded this
disease as an urgent condition that needs aggressive surgical
debridement and antifungal therapy, but there has not been any
definitive cutoff point that has been suggested thus far.
We hypothesize that an earlier treatment would be
associated with an improved survival rate. We examined the
time taken to treat patients suffering from and their subsequent survival rates and found that the time taken to treat
Table 2. Outcomes of patients stratified by the duration of symptoms.
DURATION OF SYMPTOMS

DEAD

CENSORED

PERCENT DEAD

1 to 7 days

14

30.9

8 to 14 days

10

33.3

15 to 30 days

27.3

More than 30 days

13

the patients was the most statistically significant predictor for

mortality (P=0.045). The cutoff point at 14days should be
used as the time frame where definitive treatment has to be
conducted.
Other underlying diseases such as diabetes mellitus and
immunocompromised diseases are also important factors that
contribute to the mortality rate.11,12 Our results indicate that
there was no statistically significant impact on the survival of
patients when the underlying diseases were regarded as the
covariate for the time taken to treat these patients. The lack
of covariance could be explained by the characteristics of this
cohort of patients, where the most common underlying disease was diabetes mellitus, which is a predisposing factor that
is reversible and can be rapidly managed. Another explanation
was a small sample size of patients because of the rarity of this
disease. A large-scale multicenter study is necessary to address
this problem.

Conclusions

Our study demonstrates that the time taken to treat patients

suffering from invasive fungal rhinosinusitis is an important
determinant in their outcome. Appropriate treatment should
be administered within 14days from the start of symptoms.

Acknowledgments

The authors thank the staff and nurses at Srinagarind Hospital

for their excellent care of the patients and Joel Yong for revision of the manuscript.

Author Contributions

Conceived and designed the experiments: PP, ST. Analyzed

the data: PP. Wrote the first draft of the manuscript: PP. Contributed to the writing of the manuscript: PP, ST. Agree with
manuscript results and conclusions: PP, ST. Jointly developed
the structure and arguments for the paper: PP, ST. Made critical revisions and approved final version: PP, ST. All authors
reviewed and approved of the final manuscript.

Clinical Medicine Insights: Ear, Nose and Throat 2014:7

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Piromchai and Thanaviratananich

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